The present proposal will continue the career development of Dr. Boulis as a clinician-scientist in the field of Functional Neurosurgery, focusing on an alternative to existing strategies for Neuromodulation. Neuromodulation, the manipulation of neural activity within anatomically discrete targets, is the principle tool of Functional Neurosurgery, finding application in the treatment of movement disorders, pain, spasticity, epilepsy and psychiatric disease. It has largely replaced the destruction of neural tissue as a means to treat refractory functional disorders. Nonetheless, the focused delivery of electric current is incapable of pharmacological specificity and requires electronic neural prostheses that carry a significant complication rate. Viral gene therapy has several advantages over implanted devices for the treatment of functional neural disorders. Neuronal gene expression can be achieved through minimally invasive stereotactic injection. Moreover, the tropism of viral vectors can be engineered through manipulation of the virus surface to target the vectors to individual cell types as well as limit and direct the spread of gene expression. Finally, viral gene expression can be achieved in a sustained fashion in neurons without disrupting their architecture or synaptic structure. Thus, gene transfer can be used to manipulate functioning neural structures in a fashion that current surgical procedures cannot achieve, providing the dual advantage of both pharmacologic and anatomic specificities. The following proposal explores the development of vectors to achieve controlled modulation of synaptic function using the best available inducible gene expression systems for regulated release of the clostridial tetanus toxin light (LC) gene and the inwardly rectifying potassium channel (Kir2.1) gene. Aims of the current proposal will test the following hypotheses: 1) AAV mediated LC synaptic inhibition is durable and less immunogenic than delivery mediated by Adenovirus, and that durable expression can be regulated by the Tet-on system. 2) Expression cassette modification, targeting expression to motor neurons and transgene delivery to axons, can improve the potency and specificity of LC gene-based neural inhibition. 3) The Rheoswitch(r) inducible expression system will improve controlled LC delivery. 4) Neuronal Kir2.1 gene expression can safely inhibit neuronal activity with potency exceeding that of LC mediated synaptic inhibition.